Hypertension is one of the leading causes of cardiovascular disease and stroke, accounting for nearly one-half of all deaths in the United States. Additionally, the presence of hypertension magnifies the adverse effects of renal failure and diabetes. However, the exact etiology of hypertension is unknown. To investigate mechanisms associated with the development of high blood pressure, research has increasingly incorporated rodent models of hypertension such as the Spontaneously Hypertensive Rat (SHR). Cytochrome P450 4A (CYP) is overexpressed in SHR, resulting in elevated levels of 20-HETE, a potent vasoconstrictor and natriuretic factor. However, the role of 20-HETE in the development and maintenance of hypertension in SHR is unclear. Further, it is not known whether the nervous system influences CYP expression levels in SHR. The proposed studies will explore whether CYP overexpression contributes to hypertension in both SHR and an experimental model in which hypertension is concomitantly expressed with portal hypertension and pulmonary dysfunction. The studies will examine the independent contribution of CYP overexpression on regional vascular hemodynamics and renal function in conscious animals, and will further explore a potential relationship between CYP expression levels and the nervous system. Specifically, the proposed studies will test the hypotheses that: Specific Aim 1. CYP overexpression alters both renal hemodynamics, including vascular tone, blood flow and GFR, and non-renal peripheral resistance in SHR. Specific Aim 2. The development of hypertension in SHR is driven by alterations in CYP expression secondary to increased sympathetic nervous system activity. Specific Aim 3. CYP overexpression contributes to portal hypertension and pulmonary dysfunction in hepatic denervated rats.